Pikfyve kinase inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) (shown below) useful as inhibitors of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as well as their use for treating diseases and disorders associated with PIKfyve.

This application claims the benefit of U.S. Provisional Application No.62/551,047, filed Aug. 28, 2017, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofphosphatidylinositol-3-phosphate 5-kinase (PIKfyve).

BACKGROUND OF THE INVENTION

Apilimod is recognized as a potent transcriptional inhibitor of IL-12and IL-23. See Wada et al., Blood 109 (2007):1156-1164. IL-12 and IL-23are inflammatory cytokines normally produced by immune cells, such asB-cells and macrophages, in response to antigenic stimulation.Autoimmune disorders and other disorders characterized by chronicinflammation are characterized in part by inappropriate production ofthese cytokines. In immune cells, the selective inhibition ofIL-12/IL-23 transcription by apilimod was recently shown to be mediatedby apilimod's direct binding to phosphatidylinositol-3-phosphate5-kinase (PIKfyve). See Cai et al., Chemistry and Biol. 20(2013):912-921. PIKfyve plays a role in Toll-like receptor signaling,which is important in innate immunity.

Based upon its activity as an immunomodulatory agent and a specificinhibitor of IL-12/IL-23, apilimod has been proposed as useful intreating autoimmune and inflammatory diseases and disorders. See U.S.Pat. Nos. 6,858,606 and 6,660,733 (describing a family of pyrimidinecompounds, including apilimod, purportedly useful for treating diseasesand disorders characterized by IL-12 or IL-23 overproduction, such asrheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis,psoriasis, or insulin dependent diabetes mellitus). Similarly, apilimodwas suggested to be useful for treating certain cancers based upon itsactivity to inhibit c-Rel or IL-12/23, particularly in cancers wherethese cytokines were believed to play a role in promoting aberrant cellproliferation. See WO 2006/128129 and Baird et al., Frontiers inOncology 3:1 (2013, respectively). International Publication No. WO2016/210372 and U.S. Patent Publication No. 2018/0161335, which arehereby incorporated by reference, disclose methods of treating aneurological disease such as amyotrophic lateral sclerosis with aPIKFYVE kinase inhibitor.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of the formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R¹ is hydroxy, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclyl;

each occurrence of R² is independently substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclyl;

R³ is a nitrogen- or oxygen-containing moiety;

Ring A is (i) a 5 or 6-membered heteroaryl or 5-6 or 6-5 memberedbicyclic heteroaryl, each having at least one nitrogen or oxygen ringatom, or (ii) phenyl;

L¹ is absent, C₁-C₂ alkylene, —NR^(c)—, —O—, —S—, —C(O)—, —NHC(O)—, or—C(O)NH—;

L² is —O—(CR^(a)R^(b))_(m)—, —(CR^(a)R^(b))_(m)—,—NR^(c)—(CR^(a)R^(b))_(m)—, or —S—(CR^(a)R^(b))_(m)—;

X¹ is CH, N, or CR^(c);

each occurrence of R^(a) and R^(b) are independently hydrogen, hydroxy,hydroxy(C₁₋₄)alkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclyl, halogen, nitro, —OR^(d),—SR^(d), —NR^(d)R^(e), —C(O)R^(d), —C(S)R^(d), —OC(O)R^(d), —SC(O)R^(d),OC(S)R^(d), SC(S)R^(d), —NR^(c)C(O)R^(d), —NR^(c)C(S)R^(d), —SO₂R^(c),—S(O)R^(c), —NR^(c)SO₂R^(d), —(O)₂R^(d), —OP(O)R^(d)R^(e), or—P(O)R^(d)R^(e);

R^(c) is a hydrogen or C₁₋₆ alkyl (e.g., C₁-C₄ alkyl);

each occurrence of R^(d) and R^(e) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclyl;

m is 1-4; and

p is 1 or 2.

These compounds are useful as PIKfyve kinase inhibitors.

In one embodiment, R¹ is heterocyclyl or heteroaryl. For example, R¹ maybe selected from (the squiggly lines indicate the point of attached tothe rest of the molecule)

In another embodiment, R¹ is hydroxy.

In one embodiment, each occurrence of R² is independently substituted orunsubstituted aryl, such as a substituted or unsubstituted phenyl. Forinstance, R² may be phenyl, a halogen-substituted phenyl, analkyl-substituted phenyl (e.g., a C₁₋₄ alkyl-substituted phenyl), ahalogenated alkyl-substituted phenyl, or an alkoxy-substituted phenyl.In one embodiment, R² is selected from phenyl, 3-methoxyphenyl,3-methylphenyl, 3-trifluoromethylphenyl, and 3-chlorophenyl. In apreferred embodiment, R² is selected from phenyl, 3-methoxyphenyl, and3-methylphenyl.

In another embodiment, each occurrence of R² is independentlysubstituted or unsubstituted alkyl (such as a C₁₋₄ alkyl). For instance,R² can be unsubstituted isopropyl.

In one embodiment, R³ is a substituted or unsubstituted, saturated orunsaturated nitrogen- or oxygen-containing heterocyclyl. For instance,R³ can be a substituted or unsubstituted, saturated or unsaturated 5-10membered (such as a 5-8 membered) mono- or bi-cyclic heterocyclyl havingat least one nitrogen or oxygen ring atom. In one embodiment, R³ is asubstituted or unsubstituted 5-10 membered (such as a 5-8 membered)mono- or bi-cyclic heterocyclyl having at least one nitrogen atom andoptionally an oxygen ring atom, where the nitrogen ring atom is directlyattached to the rest of the molecule. In one preferred embodiment, R³ isa substituted or unsubstituted (unsaturated) 5-membered monocyclicheterocyclyl having an oxygen ring atom or a nitrogen ring atom.

In another embodiment, R³ is a substituted or unsubstituted, saturatedor unsaturated 6-membered monocyclic heterocyclyl having an oxygen ringatom and optionally a nitrogen ring atom. In yet another embodiment, R³is a saturated 8-membered bicyclic heterocyclyl having a nitrogen ringatom and an oxygen ring atom. In one embodiment, R³ is selected from

In one preferred embodiment, R³ is selected from

In another preferred embodiment, R³ is

In yet another embodiment, R³ is a sulfonyl group of the formula—S(O)(CH₂)_(q)OR⁴, where R⁴ is hydrogen or C₁-C₄ alkyl and q is 1-4.

In one embodiment, ring A is a 5-membered heteroaryl having at least onenitrogen ring atom. In one preferred embodiment, ring A includes twoheteroatoms as ring atoms (such as two nitrogen ring atoms, or onenitrogen ring atom with one sulfur ring atom). In another preferredembodiment, ring A is selected from

For instance, ring A can be selected from

In one preferred embodiment, the R² group in ring A above is selectedfrom substituted or unsubstituted aryl, such as a substituted orunsubstituted phenyl. For instance, R² may be phenyl, analkyl-substituted, or an alkoxy-substituted phenyl. In a preferredembodiment, R² is selected from phenyl, 3-methoxyphenyl, and3-methylphenyl.

In one embodiment, L¹ is absent.

In another embodiment, L¹ is —NH—, —N(CH₃)—, —O—, or —CH₂—. In oneembodiment, L¹ is —NH—. In another embodiment, L¹ is —C(O)NH— (where thecarbonyl is attached to the rest of the molecule and the nitrogen isattached to ring A). In yet another embodiment, L¹ is —NHC(O)— (wherethe nitrogen atom is attached to the rest of the molecule and thecarbonyl is attached to ring A).

In one embodiment, L² is —O—(CR^(a)R^(b))_(m)—. In one preferredembodiment, L² is —OCH₂CH₂— or —OCH₂—. In another embodiment, L² is—OCH₂CH₂CH(OH)CH₂—.

In another embodiment, L² is —(CR^(a)R^(b))_(m)—. In one preferredembodiment, L² is —CH₂CH₂—.

In yet another embodiment, L² is —NR^(c)—(CR^(a)R^(b))_(m)—, such as—NH—(CR^(a)R^(b))_(m)— (e.g., —NH—, —NHCH₂—, and —NHCH₂CH₂—).

In one embodiment, -L²-R¹ is —OCH₂CH₂CH(OH)CH₂OH.

In one preferred embodiment, X¹ is CH. In another embodiment, X¹ is N.

In one embodiment, each occurrence of R^(a) and R^(b) are independentlyhydrogen, hydroxy, or hydroxy(C₁₋₄)alkyl. In another embodiment, eachoccurrence of R^(a) and R^(b) are independently hydrogen or hydroxy.

In one embodiment, m is 1. In another embodiment, m is 2. In a preferredembodiment, m is 1 or 2 when R¹ is cyclic. In another preferredembodiment, m is 3 or 4 when R¹ is acyclic.

In a preferred embodiment, p is 1.

In another embodiment, p is 2.

In one preferred embodiment, the moiety

is selected from

Another embodiment is a compound of the formula (II)

or a pharmaceutically acceptable salt thereof, wherein

R¹ is hydroxy, substituted or unsubstituted heteroaryl, or substitutedor unsubstituted heterocyclyl;

R² is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclyl;

R³ is a substituted or unsubstituted oxygen-containing heterocyclyl;

Ring A is a 5-membered heteroaryl having at least one nitrogen ringatom;

L² is —O—(CR^(a)R^(b))_(m)—;

each occurrence of R^(a) and R^(b) are independently hydrogen, hydroxy,or hydroxy(C₁₋₄)alkyl; and

m is 1-4.

In one embodiment of the compound of formula (II), R¹ is heterocyclyl orheteroaryl. For example, R¹ may be selected from

In one embodiment of the compound of formula (II), R² is substitutedphenyl, such as an alkoxy-substituted phenyl, halogen-substitutedphenyl, or alkyl-substituted phenyl. For example, R² can bemethoxyphenyl (e.g., 3-methoxyphenyl) or methylphenyl (e.g.,3-methylphenyl).

In another embodiment of the compound of formula (II), R² is hydroxy.

In one preferred embodiment of the compound of formula (II), R³ isselected from

In another preferred embodiment, R³ is

In another preferred embodiment, R³ is

In one embodiment of the compound of formula (II), ring A is a5-membered heteroaryl having (i) two nitrogen ring atoms or (ii) onenitrogen ring atom and one sulfur ring atom. In another embodiment, ringA is selected from

In one embodiment of the compound of formula (II), L² is —OCH₂—,—OCH₂CH₂—, —OCH₂CH₂CH(OH)CH₂—, or —CH₂CH₂—. In one preferred embodiment,L² is —OCH₂—, —OCH₂CH₂—, or —OCH₂CH₂CH(OH)CH₂—.

Exemplary compounds of the present include those listed below andpharmaceutically salts thereof.

Another embodiment is a method of inhibiting PIKfyve in a subject (suchas a human subject) in need thereof comprising administering aneffective amount of a compound of the present invention.

Yet another embodiment is a method for treating a disease or disorderassociated with PIKfyve in a human subject in need thereof comprisingadministering an effective amount of a compound of the present inventionto the subject.

Yet another embodiment is a method of treating a subject having aneurological disease comprising administering to the subject aneffective amount of a compound of the present invention to the subject.In one embodiment, the neurological disease is amyotrophic lateralsclerosis (ALS). In another embodiment, the neurological disease isfrontotemporal dementia (FTD). In yet another embodiment, theneurological disease is Alzheimer's disease. In yet another embodiment,the neurological disease is Parkinson's disease. In yet anotherembodiment, the neurological disease is Huntington's disease. In yetanother embodiment, the neurological disease is Charcot-Marie-Toothdisease (CMT).

In one embodiment, the effective amount of the compound is the amounteffective to inhibit cellular PIKfyve activity in target cells in thesubject. In another embodiment, the effective amount is the amounteffective to induce vacuolization and disrupts intracellular traffickingin target cells.

In one embodiment, the target cell is a cancer cell. In one embodiment,the cancer cell is a lymphoma cell. In one embodiment, the lymphoma cellis a non-Hodgkin's lymphoma cell.

In one embodiment, the disease of disorder is selected from a cancer, aviral infection, or a cell proliferative disorder. For example, thecancer can be a lymphoma or melanoma. In one embodiment, the cancer isrefractory or resistant to standard therapy. In one embodiment, thecancer is a non-Hodgkin's lymphoma.

One embodiment is a method of treating a viral infection in a subject inneed thereof comprising administering an effective amount of a compoundof the present invention to the subject. The viral infection can becaused by any type of virus such as RNA and DNA viruses. In oneembodiment, the virus is Ebola virus. In another embodiment, the virusis middle east respiratory syndrome virus (MERS). In yet anotherembodiment, the virus is JC polyomavirus (JC). In yet anotherembodiment, the virus is BK polyomavirus (BK). In yet anotherembodiment, the virus is Herpes Simplex Virus (HSV). In yet anotherembodiment, the virus is Marburg virus (MarV). In yet anotherembodiment, the virus is Venezuelan equine encephalitis virus (VEEV). Inyet another embodiment, the virus is Lymphocytic choriomeningitis virus(LCMV).

Another embodiment is method of treating Charcot-Marie-Tooth disease(CMT) in a subject, preferably a human subject, in need of suchtreatment, by administering an effective amount of a compound of thepresent invention to the subject.

One embodiment is a method for treating a lymphoma comprisingadministering (e.g., an effective amount of) a compound of the presentinvention and at least one additional active agent. In one embodiment,the at least one additional active agent is selected from ibrutinib,rituximab, doxorubicin, prednisolone, vincristine, velcade, andeverolimus, and combinations thereof. In one embodiment, the methodincludes a therapeutic regimen comprising administering a compound ofthe present invention and a CHOP regimen.

In one embodiment, the method is a method for treating melanoma and themethod further comprises administering at least one additional activeagent to the subject in a therapeutic regimen comprising a compound ofthe present invention and the at least one additional active agent. Inone embodiment, the at least one additional active agent is selectedfrom dacarbazine, temozolomide, Nab-paclitaxel, carmustine, cisplatin,carboplatin, or vinblastine.

In one embodiment, the method is a method for treating a viral infectionand the method further comprises administering at least one additionalactive agent to the subject in a therapeutic regimen comprising acompound of the present invention and the at least one additional activeagent. In one embodiment, the at least one additional active agent isselected from selected from the group consisting of apilimod, APY0201,and YM-201636.

In accordance with any of the methods described herein, a compound ofthe present invention may also be administered in combination with anon-therapeutic agent which mitigates one or more side effectsassociated with the compound or increases the bioavailability of thecompound. In one embodiment, the non-therapeutic agent is selected fromthe group consisting of ondansetron, granisetron, dolasetron andpalonosetron. In another aspect, the non-therapeutic agent is selectedfrom the group consisting of pindolol and risperidone. In anotheraspect, the non-therapeutic agent is selected from a cytochrome P450 3A(CYP3A) inhibitor. In one embodiment, the CYP3A inhibitor is selectedfrom ritonavir and cobicistat.

In one embodiment, the viral infection is caused by a virus selectedfrom the group consisting of measles, Ebola (EboV), Marburg (MarV),borna disease, and human immunodeficiency virus (HIV), severe acuterespiratory system virus (SARS), and middle east respiratory syndromevirus (MERS). In one embodiment, the viral infection is caused by anEboV virus.

In one embodiment, the compound is in the form a pharmaceuticalcomposition comprising the compound and at least one pharmaceuticallyacceptable carrier.

In one embodiment, the compound comprises at least 95% or at least 99%enantiomeric excess of the (R)-enantiomer. In one embodiment, thecompound comprises at least 95% or at least 99% enantiomeric excess ofthe (S)-enantiomer.

Another embodiment is pharmaceutical composition comprising a compoundof the present invention wherein the compound comprises at least 95% orat least 99% enantiomeric excess of the (R)-enantiomer or the(S)-enantiomer.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein the following definitions shall apply unless otherwiseindicated. Further, many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term “alkyl”, unless otherwise specified, refers to a straight orbranched hydrocarbon chain radical consisting solely of carbon andhydrogen atoms, containing no unsaturation, having from one to eightcarbon atoms, and which is attached to the rest of the molecule by asingle bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl),n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term “C₁₋₆alkyl” refers to an alkyl group as defined above having up to 6 carbonatoms. The term “C₁₋₃ alkyl” refers to an alkyl group as defined abovehaving up to 3 carbon atoms. In appropriate circumstances, the term“alkyl” refers to a hydrocarbon chain radical as mentioned above whichis bivalent.

The term “alkenyl”, unless otherwise specified, refers to an aliphatichydrocarbon group containing one or more carbon-carbon double bonds andwhich may be a straight or branched or branched chain having about 2 toabout 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl),iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. The term“C₂₋₆ alkenyl” refers to an alkenyl group as defined above having up to6 carbon atoms. In appropriate circumstances, the term “alkenyl” refersto a hydrocarbon group as mentioned above which is bivalent.

The term “alkynyl”, unless otherwise specified, refers to a straight orbranched chain hydrocarbyl radical having at least one carbon-carbontriple bond, and having in the range of 2 to up to 12 carbon atoms (withradicals having in the range of 2 to up to 10 carbon atoms presentlybeing preferred) e.g., ethynyl, propynyl, and butnyl. The term “C₂₋₆alkynyl” refers to an alkynyl group as defined above having up to 6carbon atoms. In appropriate circumstances, the term “alkynyl” refers toa hydrocarbyl radical as mentioned above which is bivalent.

The term “alkoxy” unless otherwise specified, denotes an alkyl,cycloalkyl, or cycloalkylalkyl group as defined above attached via anoxygen linkage to the rest of the molecule. The term “substitutedalkoxy” refers to an alkoxy group where the alkyl constituent issubstituted (i.e., -0-(substituted alkyl). For example “alkoxy” refersto the group —O-alkyl, including from 1 to 8 carbon atoms of a straight,branched, cyclic configuration and combinations thereof attached to theparent structure through an oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. Inappropriate circumstances, the term “alkoxy” refers to a group asmentioned above which is bivalent.

The term “cycloalkyl”, unless otherwise specified, denotes anon-aromatic mono or multicyclic ring system of about 3 to 12 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.Examples of multicyclic cycloalkyl groups include perhydronaphthyl,adamantyl and norbornyl groups, bridged cyclic groups, andsprirobicyclic groups, e.g., sprio (4,4) non-2-yl. The term “C₃₋₆cycloalkyl” refers to a cycloalkyl group as defined above having up to 6carbon atoms.

The term “cycloalkylalkyl”, unless otherwise specified, refers to acyclic ring-containing radical containing in the range of about 3 up to8 carbon atoms directly attached to an alkyl group which is thenattached to the main structure at any carbon from the alkyl group, suchas cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term “cycloalkenyl”, unless otherwise specified, refers to cyclicring-containing radicals containing in the range of about 3 up to 8carbon atoms with at least one carbon-carbon double bond such ascyclopropenyl, cyclobutenyl, and cyclopentenyl. The term“cycloalkenylalkyl” refers to a cycloalkenyl group directly attached toan alkyl group which is then attached to the main structure at anycarbon from the alkyl group.

The term “aryl”, unless otherwise specified, refers to aromatic radicalshaving in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl,tetrahydronaphthyl, indanyl, and biphenyl.

The term “arylalkyl”, unless otherwise specified, refers to an arylgroup as defined above directly bonded to an alkyl group as definedabove, e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring”, unless otherwise specified, refers to anon-aromatic 3 to 15 member ring radical which consists of carbon atomsand at least one heteroatom selected from nitrogen, phosphorus, oxygenand sulfur. For purposes of this invention, the heterocyclic ringradical may be a mono-, bi-, tri- or tetracyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized. Theheterocyclic ring radical may be attached to the main structure at anyheteroatom or carbon atom.

The term “heterocyclyl”, unless otherwise specified, refers to aheterocylic ring radical as defined above. The heterocylcyl ring radicalmay be attached to the main structure at any heteroatom or carbon ringatom. In appropriate circumstances, the term “heterocyclyl” refers to ahydrocarbon chain radical as mentioned above which is bivalent.

The term “heterocyclylalkyl”, unless otherwise specified, refers to aheterocylic ring radical as defined above directly bonded to an alkylgroup. The heterocyclylalkyl radical may be attached to the mainstructure at any carbon atom in the alkyl group. Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

The term “heteroaryl”, unless otherwise specified, refers to anoptionally substituted 5 to 14 member aromatic ring having one or moreheteroatoms selected from N, O, and S as ring atoms. The heteroaryl maybe a mono-, bi- or tricyclic ring system. Examples of such “heteroaryl”radicals include, but are not limited to, oxazolyl, thiazolyl,imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl,benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl,quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl,pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamo holinyl,thiamorpholinyl sulfoxide, thiamo holinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl.

The term “5 or 6-membered heteroaryl” refers to a heteroaryl having 5-or 6-ring atoms. The term “5-6 or 6-5 membered bicyclic heteroaryl”refers to a bicyclic heteroaryl with a five-membered ring fused to asix-membered ring, where the 5-membered ring is bound to the rest of themolecule (referred as a “5-6 membered bicyclic heteroaryl”) or the6-membered ring is bound to the rest of the molecule (referred as a “6-5membered bicyclic heteroaryl”).

The heteroaryl ring radical may be attached to the main structure at anyheteroatom or carbon atom. The term “substituted heteroaryl” alsoincludes ring systems substituted with one or more oxide (—O—)substituents, such as pyridinyl N-oxides.

The term “heteroarylalkyl”, unless otherwise specified, refers to aheteroaryl ring radical as defined above directly bonded to an alkylgroup. The heteroarylalkyl radical may be attached to the main structureat any carbon atom from alkyl group.

The term “cyclic ring” refers to a cyclic ring containing 3 to 10 carbonatoms.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents which may be the same or different and are independentlyselected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heteroarylalkyl, substituted or unsubstitutedheterocyclic ring, substituted heterocyclylalkyl ring, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)RX,—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), ═N—NR^(x)R^(y), —NR^(x)C(O)OR^(y),—NR^(x)R^(y), —NR^(x)C(O)R^(y), —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z),—SONR^(x)R^(y), —SO₂NR^(x)R^(y), —OR^(x), —OR^(x)C(O)NR^(y)R^(z),—OR^(x)C(O)OR^(y), —OC(O)R^(x), —OC(O)NR^(x)R^(y),—R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR^(y),—R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), and —ONO₂, wherein R^(x), R^(y) and R^(z) in eachof the above groups can be hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted amino, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic ring, or substituted heterocyclylalkyl ring,or any two of R^(x), R^(y) and R^(z) may be joined to form a substitutedor unsubstituted saturated or unsaturated 3-10 membered ring, which mayoptionally include heteroatoms which may be the same or different andare selected from O, NR^(x) (e.g., R^(x) can be hydrogen or C₁₋₆ alkyl)or S. Substitution or the combinations of substituents envisioned bythis invention are preferably those that result in the formation of astable or chemically feasible compound. The term stable as used hereinrefers to the compounds or the structure that are not substantiallyaltered when subjected to conditions to allow for their production,detection and preferably their recovery, purification and incorporationinto a pharmaceutical composition. The substituents in theaforementioned “substituted” groups cannot be further substituted. Forexample, when the substituent on “substituted alkyl” is “substitutedaryl”, the substituent on “substituted aryl” cannot be “substitutedalkenyl”.

The term “halo”, “halide”, or, alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, and nitroethyl. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

Certain of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms andintermediate mixtures. Non-limiting examples of intermediate mixturesinclude a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80,or 22:78. Optically active (R)- and (S)-isomers can be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms and mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

The term “prodrug” refers to a compound, which is an inactive precursorof a compound, converted into its active form in the body by normalmetabolic processes. Prodrug design is discussed generally in Hardma, etal. (Eds.), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion isprovided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987). To illustrate, prodrugs can be converted into apharmacologically active form through hydrolysis of, for example, anester or amide linkage, thereby introducing or exposing a functionalgroup on the resultant product. The prodrugs can be designed to reactwith an endogenous compound to form a water-soluble conjugate thatfurther enhances the pharmacological properties of the compound, forexample, increased circulatory half-life. Alternatively, prodrugs can bedesigned to undergo covalent modification on a functional group with,for example, glucuronic acid, sulfate, glutathione, amino acids, oracetate. The resulting conjugate can be inactivated and excreted in theurine, or rendered more potent than the parent compound. High molecularweight conjugates also can be excreted into the bile, subjected toenzymatic cleavage, and released back into circulation, therebyeffectively increasing the biological half-life of the originallyadministered compound.

Additionally, the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium or tritium, or thereplacement of a carbon by ¹³C- or ¹⁴C-enriched carbon.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium, iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). All isotopic variations of the compounds of the presentinvention, whether radioactive or not, are encompassed within the scopeof the present invention.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, and thiamine; chiral bases suchas alkylphenylamine, glycinol, and phenyl glycinol; salts of naturalamino acids such as glycine, alanine, valine, leucine, isoleucine,norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, and serine; quaternaryammonium salts of the compounds of invention with alkyl halides, andalkyl sulphates. Salts may include acid addition salts where appropriatewhich are sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates,citrates, fumarates, succinates, palmoates, methanesulphonates,benzoates, salicylates, benzenesulfonates, ascorbates,glycerophosphates, and ketoglutarates. Salts can be formed by methodsknown in the art.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to an animal so that both agentsand/or their metabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried. In one embodiment, theamount of compound administered ranges from about 0.1 mg to 5 g, fromabout 1 mg to 2.0 g, from about 100 mg to 1.5 g, from about 200 mg to1.5 g, from about 400 mg to 1.5 g, and from about 400 mg to 1.0 g.

As used herein, the term “treating” refers to an approach for obtainingbeneficial or desired results including but not limited to therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient may still be afflicted withthe underlying disorder. For prophylactic benefit, the compositions maybe administered to a patient at risk of developing a particular disease,or to a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “pharmaceutically acceptable excipient” includes, but is notlimited to, any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, one or more suitable diluents, fillers, salts, disintegrants,binders, lubricants, glidants, wetting agents, controlled releasematrices, colorants/flavoring, carriers, buffers, stabilizers,solubilizers, and combinations thereof. Except insofar as anyconventional media or agent is incompatible with the active ingredient,its use in the therapeutic compositions of the invention iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions.

A “subject” includes a mammal. The mammal can be e.g., any mammal, e.g.,a human, primate, vertebrate, bird, mouse, rat, fowl, dog, cat, cow,horse, goat, camel, sheep or a pig. Preferably, the mammal is a human.The term “patient” refers to a human subject.

In accordance with the methods described herein, a “subject in need of”is a subject having a disease, disorder or condition, or a subjecthaving an increased risk of developing a disease, disorder or conditionrelative to the population at large. The subject in need thereof can beone that is “non-responsive” or “refractory” to a currently availabletherapy for the disease or disorder, for example cancer. In thiscontext, the terms “non-responsive” and “refractory” refer to thesubject's response to therapy as not clinically adequate to relieve oneor more symptoms associated with the disease or disorder. In one aspectof the methods described here, the subject in need thereof is a subjecthaving cancer whose cancer is refractory to standard therapy or whosecancer has recurred following standard treatment.

Pharmaceutical Compositions

One embodiment is a pharmaceutical composition suitable for use in asubject, such as a human. The pharmaceutical composition may comprise atleast one pharmaceutically acceptable excipient or carrier.

The pharmaceutical composition may also include at least one additionalactive agent, such as an alkylating agent, an intercalating agent, atubulin binding agent, a corticosteroid, or any combination of any ofthe foregoing. Examples of additional active agents include, but are notlimited to, ibrutinib, rituximab, doxorubicin, prednisolone,vincristine, velcade, and everolimus, In one embodiment, the at leastone additional active agent is a therapeutic agent selected fromcyclophosphamide, hydroxydaunorubicin (also referred to as doxorubicin)vincristine, prednisone, prednisolone, and any combination of any of theforegoing.

The pharmaceutical composition may include one or more non-therapeuticagents, such as ondansetron, granisetron, dolasetron, palonosetron,pindolol, risperidone, or any combination of any of the foregoing.

A pharmaceutical composition can be provided as adosage unit form, suchas an ampoule, a vial, a suppository, a dragee, a tablet, or a capsule.

The pharmaceutical compositions can take any suitable form (e.g,liquids, aerosols, solutions, inhalants, mists, sprays; or solids,powders, ointments, pastes, creams, lotions, gels, patches and the like)for administration by any desired route (e.g, pulmonary, inhalatison,intranasal, oral, buccal, sublingual, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal,transdermal, transmucosal, rectal, and the like). For example, apharmaceutical composition of the invention may be in the form of anaqueous solution or powder for aerosol administration by inhalation orinsufflation (either through the mouth or the nose), in the form of atablet or capsule for oral administration; in the form of a sterileaqueous solution or dispersion suitable for administration by eitherdirect injection or by addition to sterile infusion fluids forintravenous infusion; or in the form of a lotion, cream, foam, patch,suspension, solution, or suppository for transdermal or transmucosaladministration.

A pharmaceutical composition can be in the form of an orally acceptabledosage form including, but not limited to, capsules, tablets, buccalforms, troches, lozenges, and oral liquids in the form of emulsions,aqueous suspensions, dispersions or solutions. Capsules may containmixtures of a compound of the present invention with inert fillersand/or diluents such as the pharmaceutically acceptable starches (e.g.,corn, potato or tapioca starch), sugars, artificial sweetening agents,powdered celluloses, such as crystalline and microcrystallinecelluloses, flours, gelatins, gums, etc. In the case of tablets for oraluse, carriers which are commonly used include lactose and corn starch.Lubricating agents, such as magnesium stearate, can also be added. Fororal administration in a capsule form, useful diluents include lactoseand dried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the compound of the present invention may besuspended or dissolved in an oily phase is combined with emulsifyingand/or suspending agents. If desired, certain sweetening and/orflavoring and/or coloring agents may be added.

A pharmaceutical composition can be in the form of a tablet. The tabletcan comprise a unit dosage of a compound of the present inventiontogether with an inert diluent or carrier such as a sugar or sugaralcohol, for example lactose, sucrose, sorbitol or mannitol. The tabletcan further comprise a non-sugar derived diluent such as sodiumcarbonate, calcium phosphate, calcium carbonate, or a cellulose orderivative thereof such as methyl cellulose, ethyl cellulose,hydroxypropyl methyl cellulose, and starches such as corn starch. Thetablet can further comprise binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures.

Preparation of the Compounds

The compounds of the present invention may be prepared as follows.

Starting intermediate A-1 is oxidized, for example by reaction withm-CPBA (meta-chloroperoxybenzoic acid) in a solvent, such asdichloromethane, to produce intermediate I. Intermediate I is thenreacted with R¹-L²H, for example, in the presence of a base (such asNaH) and in a solvent, such as THF, to form Intermediate A-3.Intermediate A-3 is first reacted with

and then with R³—H to form the final compound.

Methods of Treatment

The compounds of the present invention are useful as PIKfyve kinaseinhibitors.

One embodiment a method of treating a subject having a neurologicaldisease comprising administering to the subject an effective amount of acompound of the present invention (or a pharmaceutical composition ofthe present invention) to the subject. In a preferred embodiment, thesubject is a human subject. The PIKfyve kinase inhibitors describedherein may be used in the methods for treating a neurological diseasedescribed in U.S. Patent Publication No. 2018/0161335, which is herebyincorporated by reference in its entirety. For example, the neurologicaldisease may be one that has neuronal death generated by intracellularaggregates.

In certain embodiments, the method includes treating amyotrophic lateralsclerosis (ALS). In certain embodiments, the method includes treatingfrontotemporal dementia (FTD). In certain embodiments, the methodincludes treating a neurological disease that is associated withaberrant endosomal trafficking. In certain embodiments, the methodincludes treating a neurological disease that is associated withaberrant lysosomal trafficking. In further embodiments, the methodincludes treating a subject who has a (GGGGCC)n repeat expansion in theC9ORF72 gene. In further embodiments, the subject is haploinsufficientfor C9ORF72. In further embodiments the method includes treatingpatients who have a 50% or greater reduction in C9ORF72 proteinactivity. In further embodiments, the method includes a C9ORF72 geneproduct that comprises a dipeptide repeat resulting from the (GGGGCC)nexpansion. In further embodiments, the method includes again-of-function or loss of function mutation resulting from the(GGGGCC)n expansion. In further embodiments, the neurological disease isassociated with neuronal hyperexcitability.

One embodiment is a method of treating a subject having amyotrophiclateral sclerosis (ALS) comprising administering to the subject(preferably a human subject) an effective amount of a compound of thepresent invention to the subject. Another embodiment is a method oftreating a subject having frontotemporal dementia (FTD) comprisingadministering to the subject (preferably a human subject) an effectiveamount of a compound of the present invention to the subject. Yetanother embodiment is a method of treating a subject having Alzheimer'sdisease comprising administering to the subject (preferably a humansubject) an effective amount of a compound of the present invention tothe subject. Yet another embodiment is a method of treating a subjecthaving Parkinson's disease comprising administering to the subject(preferably a human subject) an effective amount of a compound of thepresent invention to the subject. Yet another embodiment is a method oftreating a subject having Huntington's disease comprising administeringto the subject (preferably a human subject) an effective amount of acompound of the present invention to the subject. Yet another embodimentis a method of treating a subject having Charcot-Marie-Tooth disease(CMT) comprising administering to the subject (preferably a humansubject) an effective amount of a compound of the present invention tothe subject.

The method may further comprise also administering an effective amountof a potassium channel activator, an inhibitor of a glutamate receptor(such as the receptor NMDA, AMPA, or kainite) (e.g., AP5, CNQX, andNBQX), or any combination of any of the foregoing.

PIKfyve is a phosphoinositide kinase (PIK) that contains a FYVE-typezinc finger domain, which binds phosphatidylinositol 3-phosphate (PI3P).PIKfyve phosphorylates PUP to produce PI(3,5)P₂, which is involved incellular processes including membrane trafficking and cytoskeletalreorganization. The inhibition of PIKfyve by a compound described hereinis useful in treating not only cancer, but also Charcot-Marie-Toothdisease and certain viral infections, such as those caused by a virusselected from measles, Ebola virus (EboV), Marburg virus (MarV), bornadisease, and human immunodeficiency virus (HIV), severe acuterespiratory system virus (SARS), middle east respiratory syndrome virus(MERS), JC polyomavirus (JC), BK polyomavirus (BK), Herpes Simplex Virus(HSV), Venezuelan equine encephalitis virus (VEEV) and Lymphocyticchoriomeningitis virus (LCMV). The viral infection can be caused by anytype of virus such as RNA and DNA viruses.

One embodiment is a method of treating a viral infection in a subject inneed thereof comprising administering an effective amount of a compoundof the present invention to the subject. In one embodiment, the virus isEbola virus. In another embodiment, the virus is middle east respiratorysyndrome virus (MERS). In yet another embodiment, the virus is JCpolyomavirus (JC). In yet another embodiment, the virus is BKpolyomavirus (BK). In yet another embodiment, the virus is HerpesSimplex Virus (HSV). In yet another embodiment, the virus is Marburgvirus (MarV). In yet another embodiment, the virus is Venezuelan equineencephalitis virus (VEEV). In yet another embodiment, the virus isLymphocytic choriomeningitis virus (LCMV).

One embodiment is a method for treating a cell proliferative disease, acancer, or a viral infection in a subject, preferably a human subject,in need of such treatment, by administering an effective amount of acompound of the present invention or a pharmaceutical compositioncomprising same, to the subject.

The compounds described herein are useful for treating cancer. In oneembodiment, the cancer is brain cancer, glioma, sarcoma, breast cancer,lung cancer, non-small-cell lung cancer, mesothelioma, appendicealcancer, genitourinary cancers, renal cell carcinoma, prostate cancer,bladder cancer, testicular cancer, penile cancer, cervical cancer,ovarian cancer, von Hippel Lindau disease, head and neck cancer,gastrointestinal cancer, hepatocellular carcinoma, gallbladder cancer,esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer,neuroendocrine tumors, thyroid tumor, pituitary tumor, adrenal tumor,hematological malignancy, or leukemia. In another embodiment, the canceris B cell lymphoma. In another embodiment, the cancer is a melanoma.

In one embodiment the cancer is a lymphoma. In one embodiment, thelymphoma is a B cell lymphoma. In one embodiment, the B cell lymphoma isselected from the group consisting of a Hodgkin's B cell lymphoma and anon-Hodgkin's B cell lymphoma. In one embodiment, the B cell lymphoma isa non-Hodgkin's B cell lymphoma selected from the group consisting ofDLBCL, follicular lymphoma, marginal zone lymphoma (MZL) or mucosaassociated lymphatic tissue lymphoma (MALT), small cell lymphocyticlymphoma (overlaps with chronic lymphocytic leukemia) and mantle celllymphoma. In one embodiment, the B cell lymphoma is a non-Hodgkin's Bcell lymphoma selected from the group consisting of Burkitt's lymphoma,Primary mediastinal (thymic) large B-cell lymphoma, Lymphoplasmacyticlymphoma, which may manifest as Waldenstrom macroglobulinemia, Nodalmarginal zone B cell lymphoma (NMZL), Splenic marginal zone lymphoma(SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma,Lymphomatoid granulomatosis, T cell/histiocyte-rich large B-celllymphoma, Primary central nervous system lymphoma, Primary cutaneousdiffuse large B-cell lymphoma, leg type (Primary cutaneous DLBCL, legtype), EBV positive diffuse large B-cell lymphoma of the elderly,Diffuse large B-cell lymphoma associated with inflammation,Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma,and Plasmablastic lymphoma.

In one embodiment, the method is a method of treating a lymphoma using acombination therapy comprising a compound of the present invention and achemotherapy regimen for the treatment of the lymphoma. In oneembodiment, the chemotherapy regimen is the CHOP regimen. In anotherembodiment, the chemotherapy regimen is selected from COOP, CVP, EPOCH,Hyper-CVAD, ICE, R-CHOP, and R-CVP.

In the methods described here, the compounds can be administered by anysuitable route, such as an oral, intravenous, or subcutaneous route.

EXAMPLES

The examples are illustrative only and do not limit the claimedinvention.

Synthesis of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (Intermediate I)

To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (9.75 g, 50 mmol)in dichloromethane (DCM) was slowly added meta-chloroperoxybenzoic acid(mCPBA) 22.4 g, 130 mmol) at 0° C. The reaction was allowed to warm toroom temperature (RT) and stirred overnight. The mixture was quenchedwith an aqueous solution of IM NaOH, extracted with DCM, washed withsat. aq. NaHCO₃ as well as brine, and the organic phase dried (MgSO₄),filtered and evaporated to give Intermediate I,4,6-dichloro-2-(methylsulfonyl)pyrimidine, as a white solid (11.39 g).The product was used crude.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=0.94 min, (M+H)⁺ 227

¹H NMR (300 MHz DMSO-d6): δ 8.30 (1H, s), 3.32 (3H, s)

Synthesis of 4,6-dichloro-2-(2-pyridin-2-yl)ethoxy)pyrimidine(Intermediate II)

To a solution of Intermediate I (11.3 g, 50 mmol) in tetrahydrofuran(THF) (60 ml) was added NaH (2.9 g, 72.5 mmol). The temperature waslowered to −78° C. and 2-(pyridin-2-yl)ethan-1-ol (6.5 g, 52.5 mmol) inTHF (60 ml) was added dropwise. The reaction was stirred for 1 h at −78°C., and worked up by addition of water, followed by extraction withethyl acetate (EtOAc), dried (MgSO₄), filtered and evaporated. The crudeproduct was purified by silica gel chromatography using a gradient ofhexane:EtOAc 9:1 to hexane:EtOAc 7:3. After evaporation of the correctfractions, 6.7 g of Intermediate II,4,6-dichloro-2-(2-pyridin-2-yl)ethoxy)pyrimidine was obtained as a whitesolid.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=1.68 min, (M+H)⁺ 270

¹H NMR (300 MHz DMSO-d6): δ 8.43 (1H, d), 7.66 (2H, m), 7.22 (1H, d),7.15 (1H, m), 4.21 (2H, m), 3.29 (2H, m)

Synthesis of (3aR,6aR)-hexahydro-2H-furo[3,2-b]pyrrole (IntermediateIII)

To a solution of furan-2-carbaldehyde and ethyl 2-azidopropanoate inethanol (EtOH) was added sodium ethoxide (1.1 eq) and the reactionheated at reflux overnight. Evaporated, redissolved in ethyl acetate,and washed with sat. aq. sodium bicarbonate, the organic phase dried(MgSO₄), filtered and evaporated. The crude product was redissolved inxylene and heated at 160° C. for 4 hours, then evaporated and purifiedby silica gel chromatography (EtOAc/hexane). Re-dissolved in ACN,4-Dimethylaminopyridine (DMAP) added (0.1 eq) and Boc₂O and stirred atrt for 5 h, worked up (as before), redissolved in EtOH and hydrogenatedat 40 psi with Pd/C 105 for 2 h. Evaporated and treated with sat. aq.LiOH in THF at RT for 2 h. Evaporated and purified by LC/MS. The solidwas redissolved in TFA/DCM 1:2 and stirred and rt for 2 h, evaporated,decarboxylated by heating, purified by LC/MS and covered to the HClsalt.

¹H NMR (300 MHz DMSO-d6): δ 83.68 (3H, m), 2.79 (3H, m), 2.01 (3H, m),1.76 (2H, m)

Synthesis of4-chloro-6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidine(Intermediate IV)

To a solution of Intermediate II,4,6-dichloro-2-(2-(pyridin-2-yl)ethoxy)pyrimidine (269 mg, 1 mmol) inDMF (10 ml) was added 3-(3-methoxyphenyl)-1H-pyrazole (191 mg, 1.1 mmol)and NaH (19 mg, 1.2 mmol). The reaction was stirred at RT overnight,quenched with water, extracted with EtOAc, dried (MgSO₄), filtered,evaporated and purified by LCMS to give4-chloro-6-(3-phenyl-1H-pyrazol-1-yl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidine(Intermediate IV) (188 mg).

LC/MS (M+H)⁺ 408

¹H NMR (300 MHz DMSO-d6): δ 8.43 (1H, m), 8.09 (1H, m), 7.76 (1H, s),7.72 (2H, m), 7.47 (1H, m), 7.39 (1H, s), 7.18 (3H, m), 6.95 (1H, m),4.25 (2H, m), 3.81 (3H, S), 3.30 (2H, m),

Synthesis of(3aR,6aR)-4-(6-chloro-2-((tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Intermediate V)

To 2.8 g of Intermediate I (12.3 mml) was added NaH (770 mg, 32 mmol)and tetrahydrofuran-2-yl)methanol (1.81 g, 16 mmol) at 0° C. in THF (200ml). The reaction was stirred at 2 h at RT, and Intermediate III (1.81g, 16 mmol) added, and the reaction stirred overnight at RT. Thereaction was worked up by quenching with water, evaporation,re-dissolved in ethyl acetate, washed (saturated aq. sodiumbicarbonate), dried (MgSO₄), filtered and evaporated. The crude mixturewas purified by silica gel chromatography (hexane/ethyl acetate) to give2.2 g of Intermediate V.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.36 min, (M+H)⁺ 326

¹H NMR (300 MHz CDCl₃): δ 7.29 (s, 1H), 4.49 (m, 5H), 3.37 (m, 6H), 2.24(m, 2H), 2.13 (m, 1H), 1.90 (m, 5H)

Synthesis of4-(6-chloro-2-((tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)morpholine(Intermediate VI)

Intermediate VI was prepared by a method analogous to Intermediate V,except morpholine was added instead of Intermediate III.

LC/MS (mobile phase 5-100% ACN in 4 min), Rt=2.22 min, (M+H)⁺ 300

¹H NMR (300 MHz DMSO-d6): δ 6.62 (s, 1H), 4.19 (m, 1H), 4.14 (m, 1H),3.77 (m, 1H), 3.62 (m, 9H), 1.97 (m, 1H), 1.85 (m, 2H), 1.62 (m, 1H)

Synthesis of4-chloro-2-((tetrahydrofuran-2-yl)methoxy)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidine(Intermediate VII)

Intermediate VII was prepared by a method analogous to Intermediate IV,except tetrahydrofuran-2-yl)methanol was added in place of2-(pyridin-2-yl)ethan-1-ol to generate the equivalent of Intermediate IIand 5-(m-tolyl)-1H-pyrazole was added in place of3-(3-methoxyphenyl)-1H-pyrazole to generate Intermediate VII.

LC/MS (mobile phase 5-100% ACN in 4 min), Rt=3.52 min, (M+H)⁺ 371

¹H NMR (300 MHz DMSO-d6): δ 8.75 (s, 1H), 7.77 (s, 1H), 7.81 (d, 1H),7.68 (s, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.21 (s, 1H), 4.40 (m, 2H),2.16 (m, 1H), 3.83 (m, 1H0, 3.72 (m, 1H), 2.40 (s, 3H), 2.06 (m, 1H),1.88 (m, 2H), 1.72 (m, 1H)

Synthesis of4-chloro-2-(2-(tetrahydrofuran-2-yl)ethyl)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidine(Intermediate VIII)

Intermediate VIII was prepared by the scheme shown above.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=4.32 min, (M+H)⁺ 369

¹H NMR (300 MHz DMSO-d6): δ 8.72 (s, 1H), 7.89 (m, 2H), 7.81 (m, 1H),7.39 (m, 1H), 7.26 (m, 1H), 7.20 (s, 1H), 3.82 (m, 1H), 3.75 (m, 1H),3.60 (m, 1H), 2.90 (m, 2H), 2.40 (s, 3H), 2.00 (m, 3H), 1.82 (m, 2H),1.49 (m, 1H)

Example 1: Synthesis of3aR,6aR)-4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-((tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 1)

To a solution of Intermediate I,4,6-dichloro-2-(methylsulfonyl)pyrimidine (113 mg, 0.5 mmol) in THF (5ml), was added NaH (14 mg, 0.64 mmol) and the solution cooled to −78° C.Tetrahydrofuran-2-yl)methanol (51 mg, 0.48 mmol) was added dropwise as asolution in THF (1 ml), and the solution stirred for 1 h at −78° C.,then quenched with water, extracted with EtOAc, dried (MgSO4), filtered,evaporated and purified by silica gel chromatography (hexane/EtOAc) togive 16 mg of 4,6-dichloro-2-((tetrahydrofuran-2-yl)methoxy)pyrimidine.This was dissolved in dimethylformamide (DMF) (1 ml), NaH (4 mg, 0.18mmol) was added, followed by 5-(3-methoxyphenyl)-1H-pyrazole (16 mg,0.09 mmol), and the reaction mixture stirred for 1 h at RT. IntermediateIII (44 mg) was added, and the reaction stirred overnight at RT, thenquenched with water, extracted with EtOAc, dried (MgSO₄), filtered,evaporated and purified by LC/MS to give 8 mg of(3aR,6aR)-4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-((tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrroleCompound 1.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.91 min, (M+H)⁺ 464

Example 2: Synthesis of4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-((tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)morpholine(Compound 2)

To a solution of Intermediate I,4,6-dichloro-2-(methylsulfonyl)pyrimidine (113 mg, 0.5 mmol) in THF (5ml), was added NaH (14 mg, 0.64 mmol) and the solution cooled to −78° C.Tetrahydrofuran-2-yl)methanol (51 mg, 0.48 mmol) was added dropwise as asolution in THF (1 ml), and the solution stirred for 1 h at −78° C.,then quenched with water, extracted with EtOAc, dried (MgSO₄), filtered,evaporated and purified by silica gel chromatography (hexane/EtOAc) togive 23 mg of 4,6-dichloro-2-((tetrahydrofuran-2-yl)methoxy)pyrimidine.This was dissolved in DMF (3 ml), NaH (6 mg) was added, followed by5-(3-methoxyphenyl)-1H-pyrazole (16 mg) and the reaction mixture stirredfor 1 h at RT. Morpholine (9 ul) was added, and the reaction stirredovernight at rt, then quenched with water, extracted with EtOAc, dried(MgSO₄), filtered, evaporated and purified by LC/MS to give 6 mg of4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-((tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)morpholine,Compound 2.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.90 min, (M+H)⁺ 438

Example 3: Synthesis of4-(6-(3-phenyl-1H-pyrazol-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrimidin-4-yl)morpholine(Compound 3)

To a solution of Intermediate I,4,6-dichloro-2-(methylsulfonyl)pyrimidine (113 mg, 0.5 mmol) in THF (5ml), was added NaH (14 mg, 0.64 mmol) and the solution cooled to −78° C.2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (65 mg) was added dropwise as asolution in THF (1 ml), and the solution stirred for 1 h at −78° C.,then quenched with water, extracted with EtOAc, dried (MgSO₄), filtered,evaporated and purified by silica gel chromatography (hexane/EtOAc) togive 65 mg of 4-(2-(3,5-dichlorophenoxy)ethyl)tetrahydro-2H-pyran. Thiswas dissolved in DMF (3 ml), NaH (9 mg) was added, followed by5-(3-methoxyphenyl)-1H-pyrazole (41 mg) and the reaction mixture stirredfor 1 h at RT. Morpholine (21 ul) was added, and the reaction stirredovernight at rt, then quenched with water, extracted with EtOAc, dried(MgSO₄), filtered, evaporated and purified by LC/MS to give 9 mg of4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrimidin-4-yl)morpholine,Compound 3.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=4.14 min, (M+H)⁺ 466

Example 4: Synthesis of(3aR,6aR)-4-(6-(3-phenyl-1H-pyrazol-1-yl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 4)

Compound 4 was prepared by a method analogous to that for Compound 1,except Intermediate III was used in place of morpholine and5-phenyl-1H-pyrazole was used in place of5-(3-methoxyphenyl)-1H-pyrazole.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.16 min, (M+H)⁺ 455

Example 5: Synthesis of2-((4-((3aR,6aR)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)ethan-1-ol(Compound 5)

Compound 5 was prepared by a method analogous to that for Compound 1,except 2-(tert-butoxy)ethan-1-ol was added instead oftetrahydrofuran-2-yl)methanol, and the end product was treated withtrifluoroacetic acid (TFA)/DCM 1:2 for 1 h at RT and evaporated prior topurification by LC/MS.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.16 min, (M+H)⁺ 424

Example 6: Synthesis of(3aR,6aR)-4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-(2-(4-methylthiazol-5-yl)ethoxy)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 6)

Compound 6 was prepared by a method analogous to that for Compound 1,except 2-(4-methylthiazol-5-yl)ethan-1-ol was added instead oftetrahydrofuran-2-yl)methanol.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.60 min, (M+H)⁺ 505

Example 7: Synthesis of4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-(2-(4-methylthiazol-5-yl)ethoxy)pyrimidin-4-yl)morpholine(Compound 7)

Compound 7 was prepared by a method analogous to that for Compound 6,except morpholine was used in place of Intermediate III.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.56 min, (M+H)⁺ 479

Example 8: Synthesis of4-((4-((3aR,6aR)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)oxy)butane-1,2-diol(Compound 8)

To a solution of Intermediate I, (113 mg, 0.5 mmol) in THF (5 ml) wasadded NaH (18.4 mg, 0.8 mmol) and the temperature lowered to −78° C.2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol 71 ul, 0.5 mmol) in THF (1ml) was added dropwise and the reaction stirred at 1 h at −78° C.,worked up by quenching with water, extraction with EtOAc, dried (MgSO₄),filtered and evaporated. Dissolved in THF (3 ml),3-(3-methoxyphenyl)-1H-pyrazole (18 mg) and NaH (7.5 mg) were added, andthe reaction was stirred for 1 h at rt. Intermediate III (35 mg) wasadded, and the reaction stirred overnight at rt. Quenched with water,evaporated and purified on HPLC, then treated with TFA/DCM 1:2 (0.5 ml),evaporated and purified by LC/MS to give 6 mg of4-(3-((3aR,6aR)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-5-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)phenoxy)butane-1,2-diol(Compound 8).

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.20 min, (M+H)⁺ 468

Example 9: Synthesis of4-((4-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-6-morpholinopyrimidin-2-yl)oxy)butane-1,2-diol(Compound 9)

Compound 9 was prepared by a method analogous to that for Compound 8,except morpholine was used in place of Intermediate III.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.18 min, (M+H)⁺ 442

Example 10: Synthesis4-(6-(4-phenyl-1H-imidazol-1-yl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine(Compound 10)

To a solution of Intermediate II (27 mg, 0.1 mmol) in DMF (1 ml) wasadded Cs₂CO₃ (65 mg, 0.2 mmol), followed by 5-phenyl-1H-imidazole (5 mg,0.1 mmol). The reaction was stirred for 70 min at RT, and morpholine (30ul) was added and the reaction stirred for 60 min. The mixture wasevaporated and purified by LC/MS to give 18 mg of4-(6-(4-phenyl-1H-imidazol-1-yl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine(Compound 10).

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.18 min, (M+H)⁺ 429

Example 11: Synthesis of(3aR,6aR)-4-(2-((tetrahydrofuran-2-yl)methoxy)-6-(4-(m-tolyl)thiazol-2-yl)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 11)

400 mg of 4-(m-tolyl)thiazole was treated with LDA (1.1 eq) and bromine(1.5 eq) to give 2-bromo-4-(m-tolyl)thiazole.2-bromo-4-(m-tolyl)thiazole was further converted to(3aR,6aR)-4-(2-((tetrahydrofuran-2-yl)methoxy)-6-(4-(m-tolyl)thiazol-2-yl)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 11) as illustrated in the scheme above. 4 mg of product wasobtained.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.78 min, (M+H)⁺ 465Example 12: Synthesis of4-(2-((tetrahydrofuran-2-yl)methoxy)-6-(4-(m-tolyl)thiazol-2-yl)pyrimidin-4-yl)morpholine(Compound 12)

Example 12: Synthesis of4-(2-((tetrahydrofuran-2-yl)methoxy)-6-(4-(m-tolyl)thiazol-2-yl)pyrimidin-4-yl)morpholine(Compound 12)

Compound 12 was prepared by a method analogous to that for Compound 11,except Intermediate VI was added instead of Intermediate V.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=2.18 min, (M+H)⁺ 439

¹H NMR (300 MHz MeOD): δ 8.26 (s, 1H), 7.86 (m, 2H), 7.38 (m, 2H), 7.24(s, 1H), 3.35 (m, 3H), 3.94 (m, 1H), 3.80 (m, 9H), 2.47 (s, 3H), 2.01(m, 4H)

Example 13: Synthesis of4-(2-((tetrahydrofuran-2-yl)methoxy)-6-(1-(m-tolyl)-1H-pyrazol-3-yl)pyrimidin-4-yl)morpholine(Compound 13)

To 200 mg of Intermediate VI in degassed dioxane (10 ml) was addedNa₂CO₃ (1.5 eq), Pd(PPh₃)₄ (0.1 eq) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 eq).The reaction was stirred at 100° C. for 2 h under argon. The mixture wasevaporated, re-dissolved in EtOAc, washed (saturated aq. sodiumbicarbonate), dried (MgSO₄), filtered and evaporated. Re-dissolved inDMF (10 ml), 3-bromotoluene (30 eq), CuI (1 eq) and Cs₂CO₃ (1.1 eq) wereadded, and the mixture heated at 160° C. for 4 h. The mixture wasevaporated, re-dissolved in EtOAc, washed (saturated aq. bicarbonate),dried (MgSO₄), filtered, evaporated, and purified by LC/MS to give 147mg of Compound 13.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=1.52 min, (M+H)⁺ 422

¹H NMR (300 MHz MeOD): δ 8.28 (s, 1H), 7.71 (s, 1H), 7.65 (m, 1H), 7.39(m, 1H), 7.21 (d, 1H), 7.11 (m, 2H), 4.39 (m, 3H), 3.93 (m, 1H), 3.78(m, 9H), 2.49 (s, 3H), 2.00 (m, 4H)

Example 14: Synthesis of4-(2-((tetrahydrofuran-2-yl)methoxy)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,4-oxazepane(Compound 14)

To Intermediate VII in THF was added NaH (3.1 eq.) and 1,4-oxepane (3eq). The mixture was stirred at RT for 2 h. Purified by LC/MS to giveCompound 14.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.19 min, (M+H)⁺ 436

¹H NMR (300 MHz CDCl₃): δ 8.60 (s, 1H), 7.79 (s, 1H), 7.73 (m, 1H), 7.35(m, 1H), 7.20 (m, 1H) 6.88 (s, 1H), 6.76 (s, 1H), 4.43 (m, 1H), 4.34 (m,2H), 3.90 (m, 7H), 3.77 (m, 3H), 2.46 (s, 3H), 2.12 (m, 3H), 1.99 (m,2H), 1.83 (m, 1H)

Example 15: Synthesis of4-(3-methoxypyrrolidin-1-yl)-2-((tetrahydrofuran-2-yl)methoxy)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidine(Compound 15)

Compound 15 was prepared by a method analogous to that for Compound 14.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.71 min, (M+H)⁺ 436

¹H NMR (300 MHz CDCl₃): δ 8.58 (s, 1H), 7.78 (s, 1H), 7.72 (m, 1H), 7.34(m, 1H), 7.20 (m, 1H), 6.71 (d, 2H), 4.48 (m, 1H), 4.35 (m, 2H), 4.11(m, 1H), 3.97 (m, 3H), 3.69 (m, 3H), 3.41 (s, 3H), 2.43 (s, 3H), 2.26(m, 3H), 2.00 (m, 2H), 1.83 (m, 1H)

Example 16: Synthesis of(3aR,6aR)-4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 16)

Compound 16 was prepared by a method analogous to that for Compound 4,except 5-(3-methoxyphenyl)-1H-pyrazole was added instead of5-phenyl-1H-pyrazole.

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=3.89 min, (M+H)⁺ 485

Example 17: Synthesis of2-((tetrahydrofuran-2-yl)methoxy)-4-(tetrahydrofuran-3-yl)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidine(Compound 17)

To 100 mg of Intermediate VII in degassed dioxane/water 9:1 was added2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 eq), K₂CO₃(1.1 eq) and Pd(dppf)Cl₂ (0.3 eq) and the mixture was heated under argonat 90° C. overnight. The mixture was evaporated, re-dissolved in EtOAcand saturated aq. bicarbonate, the layers separated, washed withbicarbonate, dried (MgSO₄), filtered, and evaporated. Re-dissolved inEtOH, Pd/C added and hydrogenated for 4 h at RT. Purified by LC/MS.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=2.34 min, (M+H)⁺ 407

¹H NMR (300 MHz CDCl₃): δ 8.62 (s, 1H), 7.79 (s, 1H), 7.73 (d, 1H), 7.61(s, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 6.81 (s, 1H), 4.45 (m, 3H), 4.22(m, 1H), 4.12 (m, 1H), 3.85 (m, 1H), 3.61 (m, 1H), 3.39 (m, 2H), 2.49(s, 3H), 2.11 (m, 3H), 1.83 (m, 1H)

Example 18: Synthesis of4-((2-methoxyethyl)thio)-2-((tetrahydrofuran-2-yl)methoxy)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidine(Compound 18)

To 60 mg of Intermediate VII in DMF (4 ml) was added tBuOK (1.1 eq) and2-methoxyethane-1-thiol (1.2 eq) and the reaction stirred at RTovernight. The mixture was evaporated, re-dissolved in EtOAc, washedwith sat aq. NaHCO₃, dried (MgSO₄), filtered and evaporated.Re-dissolved in DCM (4 ml) and 1.5 eq of mCPBA added, stirred at RT for4 h, worked up as described for the last step and purified by LC/MS togive Compound 18.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=1.92 min, (M+H)⁺ 443

¹H NMR (300 MHz CDCl₃): δ 8.61 (1H, s), 8.33 (1H, s), 7.82 (1H, s), 7.71(1H, m), 7.35 (1H, m), 7.24 (1H, m), 6.86 (1H, s), 4.42 (3H, m), 3.90(4H, m), 3.47 (4H, m), 3.19 (1H, m), 2.48 (3H, s), 2.08 (3H, m), 1.82(1H, m)

Example 19: Synthesis of(3aR,6aR)-4-(6-(3-phenyl-1H-pyrazol-1-yl)-2-(2-(pyrimidin-2-yl)ethyl)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 19)

To 4,6-dichloro-2-(2-(pyrimidin-2-yl)ethyl)pyrimidine (22 mg, 0.09 mmol)in DMF (4 ml) was added 3-(m-tolyl)-1H-pyrazole (47 mg, 0.3 mmol) andNaH (50 mg). The mixture was shaken for 2 h at RT and(3aR,6aR)-hexahydro-412-furo[3,2-b]pyrrole (27 mg, 0.09 mmol) added. Thereaction was heated to 80° C. for 4 h and purified by LC/MS to give 7 mgof(3aR,6aR)-4-(6-(3-phenyl-1H-pyrazol-1-yl)-2-(2-(pyrimidin-2-yl)ethyl)pyrimidin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(Compound 19).

LC/MS (mobile phase 5-100% ACN in 5 min), Rt=4.02 min, (M+H)⁺ 454

Example 20: Synthesis of(4-(2-(2-(tetrahydrofuran-2-yl)ethyl)-6-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)morpholin-3-yl)methanol(Compound 20)

To 60 mg of Intermediate VIII in DMF (3 ml) was added Cs₂CO₃ (3 eq) andmorpholin-3-ylmethanol (3 eq). The reaction was heated at 100 C for 6 h,evaporated and purified by LC/MS to give 22 mg of Compound 20.

LC/MS (mobile phase 5-100% ACN in 3 min), Rt=2.03 min, (M+H)⁺ 450

¹H NMR (300 MHz DMSO-d6): δ 8.62 (1H, s), 7.80 (2H, m), 7.36 (1H, m),7.22 (1H, m), 7.03 (2H, m), 4.99 (1H, m), 4.29 (1H, b), 4.08 (1H, d),3.95 (1H, m), 3.79 (3H, m), 3.55 (4H, m), 3.76 (2H, m), 2.40 (3H, s),1.98 (3H, m), 1.82 (2H, m), 1.46 (1H, m)

Biological Activity

The activity of Compounds 1-20 was measured using a PIKFYVE assay(luciferase ADP-Glo kinase assay available from Promega Corp. ofMadison, Wis.). The activity for each compound is provided in Table 1below (“A” refers to an IC₅₀ of less than 5 nM, “B” refers to an IC₅₀ of5-100 nM, “C” refers to an IC₅₀ of 101-1,000 nM, and “D” refers to anIC₅₀ of 1,001-10,000 nM).

TABLE 1 PIKFYVE Activity Compound (IC₅₀ in nM) Compound 1 B Compound 2 ACompound 3 A Compound 4 C Compound 5 C Compound 6 B Compound 7 ACompound 8 B Compound 9 A Compound 10 D Compound 11 C Compound 12 BCompound 13 B Compound 14 C Compound 15 D Compound 16 C Compound 17 BCompound 18 D Compound 19 B Compound 20 B

All references cited herein are incorporated by reference.

1. A compound of the formula (I)

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydroxy,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclyl; each occurrence of R² isindependently substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclyl; R³ is a nitrogen- or oxygen-containing moiety; Ring A is(i) a 5 or 6-membered heteroaryl or 5-6 or 6-5 membered bicyclicheteroaryl, each having at least one nitrogen or oxygen ring atom, or(ii) phenyl; L¹ is absent, C₁-C₂ alkylene, —NR^(c)—, —O—, —S—, —C(O)—,—NHC(O)—, or —C(O)NH—; L² is —O—(CR^(a)R^(b))_(m)—, —(CR^(a)R^(b))_(m)—,—NR^(c)—(CR^(a)R^(b))_(m)—, or —S—(CR^(a)R^(b))_(m)—; X¹ is CH, N, orCR^(c); each occurrence of R^(a) and R^(b) are independently hydrogen,hydroxy, hydroxy(C₁₋₄)alkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclyl, halogen, nitro, —OR^(d), —SR^(d), —NR^(d)R^(e),—C(O)R^(d), —C(S)R^(d), —OC(O)R^(d)—SC(O)R^(d), OC(S)R^(d), SC(S)R^(d),—NR^(c)C(O)R^(d), —NR^(c)C(S)R^(d), —SO₂R^(c), —S(O)R^(c),—NR^(c)SO₂R^(d), —OS(O)₂R^(d), —OP(O)R^(d)R^(e), or —P(O)R^(d)R^(e);R^(c) is a hydrogen or C₁₋₆ alkyl; each occurrence of R^(d) and R^(e)are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclyl; m is 1-4; and p is 1 or
 2. 2. The compound of claim 1,wherein R¹ is heterocyclyl or heteroaryl.
 3. The compound of claim 1 or2, wherein R¹ is be selected from (the squiggly lines indicate the pointof attached to the rest of the molecule)


4. The compound of claim 1, wherein R¹ is hydroxy.
 5. The compound ofany of the preceding claims, wherein each occurrence of R² isindependently substituted or unsubstituted phenyl.
 6. The compound ofclaim 5, wherein R² is phenyl, a halogen-substituted phenyl, analkyl-substituted phenyl, a halogenated alkyl-substituted phenyl, or analkoxy-substituted phenyl.
 7. The compound of claim 5, wherein R² isselected from phenyl, 3-methoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, and 3-chlorophenyl.
 8. The compound of any ofthe preceding claims, wherein R³ is a substituted or unsubstituted,saturated or unsaturated nitrogen- or oxygen-containing heterocyclyl. 9.The compound of any of the preceding claims, wherein R³ is selected from


10. The compound of any of the preceding claims, wherein R³ is selectedfrom


11. The compound of any of the preceding claims, wherein ring A is a5-membered heteroaryl having at least one nitrogen ring atom.
 12. Thecompound of any of the preceding claims, wherein ring A is selected from


13. The compound of any of the preceding claims, wherein ring A can beselected from


14. The compound of any of the preceding claims, wherein L¹ is absent.15. The compound of any of the preceding claims, wherein L¹ is —NH—,—N(CH₃)—, —O—, or —CH₂—.
 16. The compound of any of the precedingclaims, wherein L² is —O—(CR^(a)R^(b))_(m)—.
 17. The compound of any ofthe preceding claims, wherein L² is —OCH₂CH₂—, —OCH₂—, or—OCH₂CH₂CH(OH)CH₂—.
 18. The compound of any of the preceding claims,wherein L² is —(CR^(a)R^(b))_(m)—.
 19. The compound of any of thepreceding claims, wherein -L²-R¹ is —OCH₂CH₂CH(OH)CH₂OH.
 20. Thecompound of any of the preceding claims, wherein X¹ is CH.
 21. Thecompound of any of the preceding claims, wherein each occurrence ofR^(a) and R^(b) are independently hydrogen, hydroxy, orhydroxy(C₁₋₄)alkyl.
 22. The compound of any of the preceding claims,wherein each occurrence of R^(a) and R^(b) are independently hydrogen orhydroxy.
 23. The compound of any of the preceding claims, wherein mis
 1. 24. The compound of any of the preceding claims, wherein m is 2.25. The compound of any of the preceding claims, wherein p is
 1. 26. Thecompound of any of the preceding claims, wherein p is
 2. 27. Thecompound of any of the preceding claims, wherein the moiety

is selected from


28. A compound of the formula (II)

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydroxy,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocyclyl; R² is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclyl; R³ is a substituted or unsubstituted oxygen-containingheterocyclyl; Ring A is a 5-membered heteroaryl having at least onenitrogen ring atom; L² is —O—(CR^(a)R^(b))_(m)—; each occurrence ofR^(a) and R^(b) are independently hydrogen, hydroxy, orhydroxy(C₁₋₄)alkyl; and m is 1-4.
 29. The compound of claim 28, whereinR¹ is heterocyclyl or heteroaryl.
 30. The compound of claim 28 or 29,wherein R¹ is selected from


31. The compound of any one of claims 28-30, wherein R² is substitutedphenyl.
 32. The compound of claim 31, wherein R² is 3-methoxyphenyl or3-methylphenyl.
 33. The compound of any one of claims 28-32, wherein R³is selected from


34. The compound of claim 33, wherein R³ is


35. The compound of claim 33, wherein R³ is


36. The compound of any one of claims 28-35, wherein ring A is a5-membered heteroaryl having (i) two nitrogen ring atoms or (ii) onenitrogen ring atom and one sulfur ring atom.
 37. The compound of any oneof claims 28-36, wherein ring A is selected from


38. The compound of any one of claims 28-37, wherein L² is —OCH₂—,—OCH₂CH₂—, —OCH₂CH₂CH(OH)CH₂—, or —CH₂CH₂—.
 39. The compound of claim38, wherein L² is —OCH₂—, —OCH₂CH₂—, or —OCH₂CH₂CH(OH)CH₂—.
 40. Acompound selected from

and pharmaceutically acceptable salts thereof.
 41. A method ofinhibiting PIKfyve in a subject in need thereof comprising administeringan effective amount of a compound of any one of claims 1-40.
 42. Amethod for treating a disease or disorder associated with PIKfyve in ahuman subject in need thereof comprising administering an effectiveamount of a compound of any one of claims 1-40.
 43. A method of treatinga subject having a neurological disease comprising administering to thesubject an effective amount of a compound of any one of claims 1-40. 44.The method of claim 43, wherein the neurological disease is amyotrophiclateral sclerosis (ALS).
 45. The method of claim 43, wherein theneurological disease is frontotemporal dementia (FTD).
 46. The method ofclaim 43, wherein the neurological disease is Alzheimer's disease. 47.The method of claim 43, wherein the neurological disease is Parkinson'sdisease.
 48. The method of claim 43, wherein the neurological disease isHuntington's disease.
 49. The method of claim 43, wherein theneurological disease is Charcot-Marie-Tooth disease (CMT).
 50. A methodof treating a viral infection in a subject in need thereof comprisingadministering an effective amount of a compound of any one of claims1-40.
 51. The method of claim 50 wherein the virus is Ebola virus. 52.The method of claim 50 wherein the virus is middle east respiratorysyndrome virus (MERS).
 53. The method of claim 50 wherein the virus isJC polyomavirus (JC).
 54. The method of claim 50 wherein the virus is BKpolyomavirus (BK).
 55. The method of claim 50 wherein the virus isHerpes Simplex Virus (HSV).
 56. The method of claim 50 wherein the virusis Marburg virus (MarV).
 57. The method of claim 50 wherein the virus isVenezuelan equine encephalitis virus (VEEV).
 58. The method of claim 50wherein the virus is Lymphocytic choriomeningitis virus (LCMV).